Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals

Definitions

• the present invention relates to novel 14- to 16-membered ring azalide derivatives and azalactam derivatives effective against gram positive and gram negative bacteria.
• the present invention also relates to synthetic intermediates for preparation thereof and method for producing the same.
• Macrolide antibiotics generally have low toxicity and can be orally administered, and therefore they are a class of clinically important antibacterial agents in the filed of therapeutic treatment of bacterial infectious diseases. Macrolide antibiotics are roughly classified into 14-membered ring macrolides and 16-membered ring macrolides according to the number of ring-constituting atoms in the lactone ring moiety which is an aglycone (non-saccharide moiety).
• azithromycin as a commercially available 15-membered ring macrolide is known (U.S. Patent Nos. 4,474,768 and 4,517,359), in which a nitrogen atom is introduced into the lactone ring.
• the ketone in the 9-position of erythromycin a 14-membered ring macrolide
• an imino ether obtained by the Beckmann rearrangement is reduced to introduce the nitrogen atom
• the macrolide derivatives containing a nitrogen atom as a ring-constituting atom of the lactone ring are presently known as azalides.
• the aforementioned azithromycin has characteristic kinetics in vivo as compared to those of the other macrolides, and has a feature of being effective to some gram negative bacteria.
• leucomycin antibiotics including derivatives thereof.
• many groups including the Kitasato Institute, Toyo Jozo Co., Ltd. (at that time) and the applicant's firm have conducted researches for improvement of efficacy thereof, and rokitamycin (J. Antibiotics, 34, 1001, 1981; J. Antibiotics, 34, 1011, 1981), miokamycin (J. Antibiotics, 29, 536, 1976, J.Antibiotics, 34, 436, 1981) and the like have been launched in the market.
• the macrolide antibiotics are useful in the treatment of bacterial infectious diseases in mammals including human, and examples include the aforementioned azithromycin, rokitamycin, miokamycin, and the like.
• Azithromycin as explained in detail above was found on the basis of the new structural conversion using erythromycin as a starting material. Therefore, a novel structural conversion by using a 16-membered ring macrolide as a starting material has been desired.
• azalides methods are reported in which an amine is generated by a ring opening reaction of the erythromycin structure, and then a 13- to 15-membered ring azalide is prepared via a coupling of the amine with an appropriate aldehyde and successive re-cyclization reaction, or the oxygen atom of the lactone moiety as the aglycone is converted to a nitrogen atom to prepare a 13- to 15-membered ring azalactam into which two nitrogen atoms are introduced into the ring (International Patent Publication WO94/15617).
• tylosin class of 16-membered ring macrolides As for the tylosin class of 16-membered ring macrolides, a report about 17-membered ring azalides is made as described above.
• the leucomycin 16-membered ring macrolides have been generally used as medicaments for humans. However, tylosins are used only as animal drugs.
• the inventors of the present invention conducted various researches on novel azalide and azalactam derivatives having a nitrogen atom in the lactone ring which are derived from leucomycin 16-membered ring macrolides.
• the inventors of the present invention used leucomycin macrolides as starting materials, placing the focus on the conjugated double bond at the 10- to 13-positions of the lactone ring thereof, to prepare novel dialdehyde intermediates by oxidative cleavage of the double bond, which had not been reported before the time, and converted the dialdehyde intermediates into aldehyde-carboxylic acid intermediates. Further, they successfully constructed the azalide and azalactam fundamental structures by a reductive coupling reaction using amines, and a subsequent re-cyclization reaction.
• the compounds provided by the present invention have a nitrogen atom at the 11th position counted counterclockwise from the 1-carbonyl group of the lactone ring, which azalides have not yet been reported so far.
• the present invention thus provides:
• the present invention provides:
• the present invention provides:
• the present invention further provides:
• the present invention further provides:
• the present invention provides:
• the compound or a pharmaceutically acceptable salt thereof of the present invention can be administered to a mammal including human requiring a prophylactic and/or therapeutic treatment of bacterial infection.
• the present invention thus provides:
• the present invention also provides:
• the azalide means a compound represented by the general formula (1) (2), or (3) which contains a lactone ring having a nitrogen atom at the 11-position as an aglycone (non-saccharide moiety).
• the azalactam means a compound represented by the general formula (1) (2), or (3) which contains a lactam ring having a nitrogen atom at the 11-position as an aglycone (non-saccharide moiety).
• Me means methyl group.
• the alkyl group and an alkyl moiety of a substituent containing the alkyl moiety is preferably a C1-6 alkyl unless otherwise specifically indicated, and group may be a linear, branched or cyclic alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, cyclopropyl, cyclobutyl and cyclopentyl, or an alkyl group consisting of a combination thereof, preferably a linear or branched alkyl group, unless otherwise indicated. More preferred examples are methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, and the
• alkyl group and an alkyl moiety of a substituent containing the alkyl moiety may optionally be substituted with hydroxyl group.
• the alkenyl or alkynyl group, or an alkenyl or alkynyl moiety of a substituent containing the moiety is preferably C2-6 unless otherwise specifically indicated, and the group may be a linear, branched or cyclic alkenyl or alkynyl such as vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1-propynyl, 2-propynyl, propargyl, 1-butynyl, 1-pentynyl and 2-butynyl, or alkenyl or alkynyl consisting of a combination thereof, preferably a linear or branched alkenyl or alkynyl group.
• Number and position of double bond or triple bond contained in the alkenyl and alkynyl moiety are not particularly limited, and double bond in the alkenyl moiety may be in cis-configuration or trans-configuration.
• More preferable examples include linear groups such as 1-propenyl, 2-propenyl, 2-butenyl and 2-propynyl, and double bond may be in cis-configuration or trans-configuration.
• the aryl group means a group derived from a 6- to 14-membered aromatic ring (monocyclic to tricyclic) not containing hetero atoms, such as phenyl group, 1-naphthyl group, 2-naphthyl group and 9-phenanthryl group.
• the 6-to 14-membered aryl group has 6 to 14 carbon atoms in the ring system.
• the 6- to 14-membered aryl group may be substituted optionally with 1 to 5 substituents selected from a halogen atom, hydroxyl group, nitro group, cyano group, trifluoromethyl group, a C1-6 alkyl group, a C1-6 acyl group, a C1-6 alkyloxycarbonyl group, a C1-6 acyloxy group, dimethylamino group, diethylamino group, a C1-6 alkoxyl group, a 6- to 10-membered aryl group (examples include phenyl group, 1-naphthyl group, 2-naphthyl group and the like, wherein bonding position is not particularly limited), a 5- to 10-membered heterocyclic group (examples include 1-imidazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-quinolinyl group, 4-quinolinyl group, 6-quinolinyl group, 8
• the aryl group may preferably be substituted with one substituent selected from fluorine atom, nitro group, methoxy group, dimethylamino group, hydroxyl group, phenyl group, 1-imidazolyl group, 1-pyrazolyl group, 1-tetrazolyl group, 5-isoxazolyl group, 2-methyl-4-thiazolyl group, 5-pyrimidinyl group, 1,2,4-triazolyl group, 2-pyridyl group, 3-pyridyl group and 4-pyridyl group.
• substituent selected from fluorine atom, nitro group, methoxy group, dimethylamino group, hydroxyl group, phenyl group, 1-imidazolyl group, 1-pyrazolyl group, 1-tetrazolyl group, 5-isoxazolyl group, 2-methyl-4-thiazolyl group, 5-pyrimidinyl group, 1,2,4-triazolyl group, 2-pyridyl group, 3-pyridyl group and 4-pyri
• the heterocyclic group means, unless otherwise specifically indicated, an aromatic or aliphatic 5- to 10-membered heterocyclic group (monocyclic or bicyclic) containing 1 to 4 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom, such as 1-imidazolyl group, 4-imidazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 3-quinolinyl group, 4-quinolinyl group, 6-quinolinyl group, 8-quinolinyl group, 4-isoquinolinyl group, 1,8-naphthyridin-3-yl group, 2-benzimidazolyl group, 2-benzothiazolyl group, 1-methyl-1,2,3,4-tetrahydroquinolin-4-yl group, 3-quinoxalinyl group, 6-quinoxalinyl group, 6-benzothiazolyl group, 2-benzoxazolyl group, 5-benzoxazolyl group, 5-
• the 5- to 10-membered heterocyclic ring contains 5 to 10 atoms in the ring system.
• the 5- to 10-membered aromatic heterocyclic group may be substituted optionally with 1 to 3 substituents selected from a halogen atom, hydroxyl group, nitro group, cyano group, trifluoromethyl group, a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkyloxycarbonyl group, a C1-6 acyloxy group, dimethylamino group, diethylamino group, a C1-6 alkoxyl groups, an arylcarbonyl group, an aryloxy group, an arylthio group, an arylamino group, aminocarbonyl group which may be substituted and a heterocyclic group (as described above).
• the heterocyclic ring may preferably be substituted with one substituent selected from 1-imidazolyl group, 4-(pyridin-3-yl)-1-imidazolyl group, 3-pyridyl group, 3-quinolinyl group, 4-quinolinyl group, 6-quinolinyl group, 8-quinolinyl group, 4-isoquinolinyl group, 6-quinoxalinyl group, 1,8-naphthyridin-3-yl group, 6-nitroquinolin-3-yl group, 6-cyanoquinolin-3-yl group, 2-benzothiazolyl group, 6-benzothiazolyl group, 5-benzofuryl group, 5-benzothienyl group, 3-benzothienyl group, 1-methyl-1,2,3,4-tetrahydroquinolin-4-yl group, 3,4-dihydro-1H-[1,8]naphthyridin-2-on-6-yl group, 5-benzo[c][1,2,5]ox
• the acyl group or an acyl moiety of a substituent containing the acyl moiety means, unless otherwise specifically indicated, a linear or branched C1-5 alkylcarbonyl group, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group and isovaleryl group.
• Preferred examples include acetyl group, propionyl group, n-butyryl group, isobutyryl group, isovaleryl group, and the like.
• the silyl type protective group means a readily removable group well known in the field which can protect hydroxyl group and be selectively removed, such as trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, and the like.
• Preferred examples include trimethylsilyl group, tert-butyldimethylsilyl group, and the like.
• the ether type protective group means a readily removable group well known in this field which can protect hydroxyl group and be selectively removed, such as ethoxyethyl group.
• Preferred examples include ethoxyethyl group, and the like.
• the acetal type protective group means, unless otherwise specifically indicated, a readily removable group well known in this field which can protect formyl group and be selectively removed, for example, non-cyclic acetals such as dimethyl acetal, diethyl acetal and diisopropyl acetal, and cyclic acetals such as ethylene acetal and propylene acetal.
• non-cyclic acetals such as dimethyl acetal, diethyl acetal and diisopropyl acetal
• cyclic acetals such as ethylene acetal and propylene acetal.
• Preferred examples include dimethyl acetal group, and the like.
• protective groups those skilled in the art can choose a suitable protective group by referring to, for example, "Protective Groups in Organic Syntheses, Ed. by P.G.M. Wuts and T. Green, 3rd edition, 1999, John Wiley & Sons, and the like.
• Protective Groups in Organic Syntheses Ed. by P.G.M. Wuts and T. Green, 3rd edition, 1999, John Wiley & Sons, and the like.
• introduction and elimination of a protective group methods described in, for example, "Handbook of Reagents for Organic Synthesis", Ed. by L.A. Paquette, 4 volumes in total, 1999, John Wiley & Sons, and the like can be referred to.
• halogen atom means, unless otherwise specifically indicated, an atom selected from fluorine, chlorine, bromine and iodine atoms. Preferred examples include fluorine atom, chlorine atom and bromine atom.
• halomethyl group means a methyl group one of which hydrogen atom is replaced with a halogen atom.
• Preferred examples include chloromethyl group, and the like.
• R 1 to R 3 , R 13 , R 3" and R 4" mentioned in the preparation scheme mentioned below have the same meanings as those defined above
• A represents a straight C2-4 alkylene chain which may be substituted with hydroxyl group, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, or an Ar-B' group (wherein Ar and B' have the same meanings as defined above), provided that the alkylene chain may contain one double bond in a C4 chain.
• the preparation methods are divided into the first to seventh steps shown in Preparation Scheme 1, each of which will be explained in detail.
• the modification of the 9-hydroxyl group of the starting material represented by the formula (5) with an acyl group can be selectively progressed by a reaction with an acid halide in methylene chloride solvent in the presence of pyridine.
• the solvent used in this reaction may be, besides methylene chloride, an aprotic solvent such as chloroform, benzene, toluene and xylene.
• the base is preferably an organic base such as pyridine, and preferably used in an amount of 1 to 10 equivalents.
• As the acylation reagent 1 to 5 equivalents of an acid halide is preferably used.
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 0.5 to 24 hours.
• the reaction progresses in a good yield.
• an organic acid such as para-toluenesulfonic acid and camphorsulfonic acid can be employed.
• PPTS pyridinium p-toluenesulfonate
• solvent methyl orthoformate, which also serves as the reagent, or a mixed solvent of methyl orthoformate and methanol is preferably used in an amount of 10 times (V/W) to 60 times (V/W).
• the reaction progresses in a sufficient yield at a temperature in the range of 20 to 80°C, and the reaction time may be 1 hour to 6 days.
• R 13 is methyl group
• the modification can be similarly carried out by using, for example, a mixed solvent of ethyl orthoformate and ethanol, a mixed solvent of isopropyl orthoformate and isopropanol, a mixed solvent of ethylene glycol and benzene, or a mixed solvent of propylene glycol and benzene, instead of the mixed solvent of methyl orthoformate and methanol.
• the successive modification of the 2'-hydroxyl group in the mycaminose moiety with acetyl group can be progressed quantitatively, for example, in an acetonitrile solvent by a reaction using acetic anhydride.
• the solvent used for this reaction may also be an aprotic solvent such as methylene chloride and chloroform, and as the acetylating agent, 1 to 5 equivalents of acetic anhydride may be preferably used.
• the reaction progresses in a good yield at a temperature in the range of 20 to 60°C, and the reaction time may be 1 to 48 hours.
• the second step of preparing the compounds represented by the formula (7) will be explained.
• the second step can be carried out by a reaction using N-methylmorpholine N-oxide as a co-oxidizing agent with a compound represented by the formula (6), for example, in a mixed solvent of acetone and water in the presence of a catalytic amount of a metal oxidizing agent.
• the metal oxidizing agent used may be potassium osmate(VI) dihydrate.
• 0.05 to 1 equivalent of osmium tetraoxide may be used.
• a chlorate such as sodium chlorate, silver chlorate and barium chlorate, hydrogen peroxide, tert-butyl hydroperoxide, and the like may be used in the presence or absence of trimethylamine N-oxide, potassium hexacyanoferrate (III), or a quarternary ammonium salt such as tetraethylammonium acetate.
• trimethylamine N-oxide potassium hexacyanoferrate (III), or a quarternary ammonium salt such as tetraethylammonium acetate.
• K hexacyanoferrate (III) potassium hexacyanoferrate
• a quarternary ammonium salt such as tetraethylammonium acetate.
• 1 to 5 equivalents of N-methylmorpholine N-oxide may be used.
• the solvent may be, besides the mixed solvent of acetone and water, acetonitrile, tetrahydrofuran, methylene chloride, tert-butyl alcohol, diethyl ether, tert-butyl alcohol, a mixed solvent of tert-butyl alcohol and water, a mixed solvent of tetrahydrofuran and water, or the like, and the reaction progresses at a temperature in the range of 0 to 50°C.
• the reaction time may be 5 hours to 3 days.
• the third step of preparing the compounds represented by the formula (8) will be explained.
• the third step can be carried out by a reaction of a compound represented by the formula (7) using lead tetraacetate as an oxidizing agent in benzene in the presence of an inorganic base.
• the oxidizing agent used for this reaction may be a peroxy acid such as sodium metaperiodate, active manganese dioxide, pyridinium chlorochlomate or the like. Preferably, 1 to 5 equivalents of lead tetraacetate may be used.
• an aprotic solvent such as benzene, toluene, xylene and methylene chloride is preferred.
• the solvent used for the reaction with a peroxy acid such as metaperiodic acid may also be water, a mixed solvent of ether and water, or a mixed solvent of methylene chloride and water.
• an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate and potassium carbonate may be preferably used.
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 5 minutes to 24 hours.
• the compound represented by the formula (8) provided by this reaction can be used for the following fourth step without purification.
• the reducing agent used for this reaction may be lithium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, zinc borohydride, or the like. Preferably, 0.5 to 2 equivalents of sodium borohydride may be used.
• the solvent used for the reaction may be, besides ethanol, a lower alcohol such as methanol and isopropanol, acetonitrile, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, or the like.
• the fourth step of preparing the compounds represented by the formula (9a) will be explained.
• This compound is provided by allowing a base to react on a compound represented by the formula (8) in, for example, acetonitrile.
• the base used in this reaction may be 1,5-diazabicyclo[4.3.0]-nonan-5-ene, 1,4-diazabicyclo[2.2.2]-octane, 4-dimethylaminopyridine, or the like.
• 1 to 5 equivalents of 1,8-diazabicyclo[5.4.0]-undecan-7-ene may be used.
• the solvent may be, besides acetonitrile, a lower alcohol such as methanol, ethanol and isopropanol, tetrahydrofuran, methylene chloride, ethyl acetate, or the like, and the solvent may be used in an amount of 1 times (V/W) to 100 times (V/W) based on the amount of the compound represented by the formula (8).
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 1 hour to 48 hours.
• the compounds represented by the formula (9a) can also be provided by treating a compound represented by the formula (8) with magnesium sulfate in benzene.
• benzene as well as methylene chloride, chloroform, diethyl ether, ethyl acetate, or the like may be used.
• the fifth step of preparing the compounds represented by the formula (10a) will be explained.
• These compounds can be provided by adding an appropriate amine to a compound represented by the formula (9a) in, for example, dimethylformamide, in the presence of molecular sieve, stirring the mixture at 0 to 50°C for 1 to 24 hours, and performing reductive amination using sodium borohydride as a reducing agent.
• RsNHAOH examples include (-)-(R)-1-(4-phenylbutylamino)-2-propanol, (R)-1-methylamino-2-propanol, 3-(4-phenylbutylamino)propanol, (-)-(R)-N-(4-hydroxypentyl)-N-(4-phenylbutyl)amine, trans-(4-phenylbutylamino)-3-penten-2-ol, 7-methylamino-1-hepten-4-ol, (-)-(S)-7-methylamino-1-hepten-4-ol, 3-methylaminomethyl-5-hexenol, (-)-(R)-N-(4-hydroxypentyl)-N-(3-(quinolin-4-yl)propyl)amine, (R)-7-methylamino-1-hepten-4-ol, (R)-7-(methylamino)hept-1-
• the reducing agent used in this reaction may be sodium triacetoxyborohydride, sodium cyanoborohydride, or the like. Preferably, 1 to 5 equivalents of sodium borohydride may be used.
• the aforementioned amine may be in the form of a salt with an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, and preferably used in an amount of 0.8 to 7 equivalents.
• the molecular sieve is preferably used in an amount of 1 time (W/W) to 10 times (W/W) based on the amount of the compound represented by the formula (9a).
• the solvent may be, dimethylformamide, as well as a lower alcohol such as methanol, ethanol and isopropanol, acetonitrile, tetrahydrofuran, methylene chloride, or the like, and preferably used in an amount of 1 time (V/W) to 50 times (V/W) based on the amount of the compound represented by the formula (9a).
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 0.5 hour to 24 hours.
• the compounds represented by the formula (10a) can also be prepared by the following method.
• the compounds can be provided by adding acetic acid and an appropriate amine to a compound represented by the formula (9a), for example, in ethanol in the presence of molecular sieve, and performing reductive amination using sodium cyanoborohydride as a reducing agent.
• the reducing agent used in this reaction may be sodium triacetoxyborohydride, sodium cyanoborohydride, or the like. Preferably, 1 to 10 equivalents of sodium cyanoborohydride may be used.
• the aforementioned amine may be in the form of a salt with an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, and preferably used in an amount of 0.8 to 7 equivalents.
• the acid to be added may be hydrochloric acid or the like. Preferably, 1 to 30 equivalents of acetic acid may be used.
• the solvent may be, ethanol, as well as a lower alcohol such as methanol and isopropanol, dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, or the like, and preferably used in an amount of 1 time (V/W) to 50 times (V/W) based on the amount of the compound represented by the formula (9a).
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 0.5 hour to 48 hours.
• a compound represented by the formula (10a) is added with 2,4,6-trichlorobenzoyl chloride, for example, in tetrahydrofuran in the presence of triethylamine, and stirred at 0 to 50°C for 1 to 24 hours to prepare a mixed acid anhydride.
• a mixed acid anhydride By adding dropwise the mixed acid anhydride prepared above to a solution of 4-dimethylaminopyridine in toluene over 5 minutes to 3 hours at 0 to 50°C to perform a cyclization reaction, the desired compounds are provided.
• the solvent used in the preparation of the mixed acid anhydride may be methylene chloride, toluene, benzene, or the like.
• tetrahydrofuran may be used in an amount of 5 to 50 times (V/W) based on the amount of the compound represented by the formula (10a).
• Triethylamine is preferably used in an amount of 1 to 5 equivalents.
• the aforementioned amine may be in the form of a salt with an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, and is preferably used in an amount of 1 to 5 equivalents.
• 2,4,6-Trichlorobenzoyl chloride is preferably used in an amount of 1 to 2 equivalents.
• 4-Dimethylaminopyridine used in the subsequent cyclization reaction is preferably used in an amount of 1 to 5 equivalents.
• the solvent benzene as well as toluene may be used, and the solvent is preferably used in an amount of 50 to 300 times (V/W) based on the amount of the compound represented by the formula (10a).
• the reaction progresses at a temperature in the range of 0 to 80°C, and the reaction time may be 0.5 to 24 hours.
• the compounds represented by the formula (11a) can also be prepared by the following method. For example, by slowly adding dropwise a solution of a compound represented by the formula (10a) in tetrahydrofuran to a solution of 2-methyl-6-nitrobenzoic anhydride and 4-dimethylaminopyridine in tetrahydrofuran to carry out a cyclization reaction, the desired compounds are provided.
• 4-dimethylaminopyridine 1-oxide, 4-pyrrolidinopyridine 1-oxide or the like alone may be used in an amount of 2 to 5 equivalents, or in addition to 2 to 5 equivalents of triethylamine, 0.1 to 0.5 equivalent of 4-dimethylaminopyridine, 4-dimethylaminopyridine 1-oxide, 4-pyrrolidinopyridine, 4-pyrrolidinopyridine 1-oxide or the like may be used.
• 2 to 5 equivalents of 4-dimethylaminopyridine may be used.
• 2-Methyl-6-nitrobenzoic anhydride is preferably used in an amount of 1 to 2 equivalents.
• the solvent may be methylene chloride, tetrahydrofuran, toluene, benzene, or the like.
• methylene chloride or tetrahydrofuran may be used in an amount of 10 to 600 times (V/W) based on the amount of the compound represented by the formula (10a).
• the solution of a compound represented by the formula (10a) in methylene chloride or tetrahydrofuran may be added dropwise over 20 minutes to 20 hours at 0 to 50°C, and after the addition, the reaction progresses at a temperature in the range of 0 to 50°C.
• the reaction time may be 0.5 to 24 hours.
• the acid anhydride used in this reaction is preferably used in an amount of 10 to 50 equivalents.
• Pyridine used as the solvent is preferably employed in an amount of 1 to 30 times (V/W) based on the amount of the compound represented by the formula (11a) wherein R 3" is hydrogen atom, and R 4" is propionyl group.
• the reaction progresses at a temperature in the range of 60 to 120°C, and the reaction time may be 5 hours to 100 hours.
• the acetal type protective group in the compound of the formula (11a) is removed by a reaction with difluoroacetic acid in a mixed solvent of acetonitrile and water to obtain a compound represented by the formula (12a) or (13a).
• R 3" is a hydrogen atom in the compounds of the formula (11a)
• these compounds can be converted into the compounds represented by the formula (12a) and/or the compounds represented by the formula (13a), and by extending the reaction time or raising the concentration of the acid used, said compounds can be converted selectively into the compounds represented by the formula (13a).
• the equivolume mixed solution of acetonitrile and water used as the solvent is preferably employed in an amount of 10 to 300 times (V/W) based on the amount of the compound represented by the formula (11a).
• the acid monofluoroacetic acid, trifluoroacetic acid, acetic acid, hydrochloric acid, or the like may be used.
• 1 to 100 equivalents of difluoroacetic acid may be used.
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 1 hour to 10 days.
• the first step of preparing the compounds represented by the formula (10b) will be explained. These compounds are provided by carrying out reductive amination using an amine having an azide for a compound represented by the formula (9a) as in the fifth step shown in Preparation Scheme 1.
• the amine having an azide used in this reaction is represented as R 3 NAN 3 , wherein and R 3 and A have the same meanings as those defined above.
• R 3 NAN 3 examples include N-(2-azidoethyl)-N-(4-phenylbutyl)amine, (R)-N-(2-azidopropyl)-N-(4-phenylbutyl)amine, N-(2-azidoethyl)-N-methylamine, (+)-(R)-N-(2-azidopropyl)-N-(4-methoxybenzyl)amine, (-)-(S)-N-(2-azidopropyl)-N-(4-methoxybenzyl)amine, N-(3-azidopropyl)-N-(4-phenylbutyl)amine, N-(3-azidobutyl)-N-(4-phenylbutyl)amine, N-(3-azidobutyl)-N-(4-methoxybenzyl)amine, N-(3-azido-5-hexen
• the second step of preparing the compounds represented by the formula (10c) will be explained.
• These compounds can be provided by performing a reduction reaction, for example, using trimethylphosphine in a mixed solvent of acetonitrile and water, for a compound represented by the formula (10b).
• These compounds can be N-alkylated as required.
• the phosphine reagent in this reaction may be tributylphosphine or the like. Preferably, 1 to 10 equivalents of triphenylphosphine or trimethylphosphine may be used. Trimethylphosphine can be used after dissolution in toluene or the like.
• the solvent may be, a mixed solvent of acetonitrile and water, as well as a mixed solvent of tetrahydrofuran and water, a mixed solvent of dioxane and water, or the like, and the solvent may be preferably used in an amount of 5 to 100 times (V/W) based on the amount of the compound represented by the formula (10b).
• the reaction progresses at a temperature in the range of 0 to 100°C, and the reaction time may be 1 hour to 3 days.
• the third step of preparing the compounds represented by the formula (11b) will be explained.
• These compounds can be provided by carrying out a cyclization reaction, for example, using diphenylphosphoryl azide in dimethylformamide in the presence of a base for a compound represented by the formula (10c).
• the diphenylphosphoryl azide in this reaction is preferably used in an amount of 1 to 5 equivalents.
• the base may be an organic base such as triethylamine and diisopropylethylamine.
• sodium hydrogencarbonate may be used in an amount of 1 to 20 equivalents.
• the solvent may be dimethylformamide, as well as tetrahydrofuran, 1,2-dimethoxyethane, or the like, and the solvent may be preferably used in an amount of 30 to 250 times (V/W) based on the amount of the compound represented by the formula (10c).
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 1 to 48 hours.
• R 1 , R 2 or R 4" may be removed simultaneously with the deacetylation at the 2'-position, depending on the reaction conditions.
• a palladium catalyst that can be used for the usual Heck reaction such as tetrakis(triphenylphosphine)palladium(0) and palladium(II) chloride can be used for this reaction.
• palladium(II) acetate or tris(dibenzylideneacetone)-dipalladium(0) may be used in an amount of 0.05 to 0.6 equivalent.
• the base to be used may be sodium carbonate, cesium carbonate, or the like.
• triethylamine, dicyclohexylmethylamine, or sodium hydrogencarbonate may be used in an amount of 1 to 5 equivalents.
• phosphine ligand As the phosphine ligand to be used, a ligand that can be used for the usual Heck reaction such as 1,3-bis(diphenylphosphino)propane, 1,4-bis-(diphenylphosphino)butane, and 1,1'-bis-(diphenylphosphino)ferrocene can be used, and 2-(di-tert-butylphosphino)biphenyl, tri-o-tolylphosphine, or tri-tert-butylphosphine is preferably used in an amount of 0.1 to 1.5 equivalents. When tetrabutylammonium chloride is used as an additive, it is not necessary to use the phosphine ligand.
• the halogen compound to be used is a compound having a halogen atom on an appropriate aryl group or heterocyclic ring ("aryl group or heterocyclic ring" mentioned herein has the same meaning as Ar mentioned above), and is preferably used in an amount of 1 to 10 equivalents.
• the halogen atom may be chlorine atom or iodine atom. Bromine atom is preferred.
• the solvent may be tetrahydrofuran, dimethyl sulfoxide, 1-methyl-2-pyrrolidone, or the like.
• acetonitrile, 1,4-dioxane, or dimethylformamide may be used in an amount of 1 to 50 times (V/W) based on the amount of the compound represented by the formula (14a).
• reaction time may be 0.5 hour to 10 days.
• reaction time may be 0.5 hour to 10 days.
• products wherein a double bond of the usual products is rearranged to the adjacent position may sometimes be produced.
• a metal catalyst that can be used for ordinary cross metathesis reactions such as (benzylidene)bis(trichlorohexylphosphine)ruthenium(IV) dichloride, and 2,6-diisopropylphenylimidoneophylidene molybdenum(VI) bis(hexafluoro-t-butoxide) can be used.
• tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium(IV) dichloride may be used in an amount of 0.05 to 0.6 equivalent.
• the olefin compound used may preferably have 2-propenyl group or 3-butenyl group on an appropriate aryl group or heterocyclic ring ("aryl group or heterocyclic ring” mentioned herein has the same meaning as Ar mentioned above), and be used in an amount of 1 to 5 equivalents.
• the solvent may be benzene, toluene, or the like, and preferably ethylene chloride may be used in an amount of 10 to 50 times (V/W) based on the amount of the compound represented by the formula (14a).
• the reaction progresses at a temperature in the range of 30 to 130°C, and the reaction time may be 1 hour to 2 days.
• the second step of preparing the compounds represented by the formula (16a) will be explained. These compound are provided by subjecting a compound represented by the formula (15a) to catalytic hydrogen reduction.
• the catalyst used for this reaction may be palladium black, palladium hydroxide, or the like.
• palladium carbon (Pd-C) may be used in an amount of 5 to 80% (W/W) based on the raw material.
• a single solvent of a lower alcohol such as methanol, ethanol and isopropanol, dioxane, water, acetonitrile, tetrahydrofuran, ethyl acetate, or the like may be used, or a mixed solvent consisting of a combination of these may be used.
• the reaction progresses at a temperature in the range of 0 to 50°C under a hydrogen atmosphere of 1 to 5 atm, and the reaction time may be 1 to 48 hours.
• a secondary amine may be produced in the heterocyclic ring in the reaction.
• the resulting secondary amine moiety can be converted into a tertiary amine by, for example, a reductive alkylation reaction using formalin or an appropriate aldehyde in ethanol in the presence of acetic acid.
• the reducing agent in this reaction may be sodium triacetoxyborohydride or the like.
• sodium cyanoborohydride may be used in an amount of 1 to 5 equivalents.
• Formalin or aldehyde used may preferably be employed in an amount of 1 to 5 equivalents, and acetic acid is preferably used in an amount of 1 to 10 equivalents.
• the solvent may be, ethanol, as well as a lower alcohol such as methanol and isopropanol, acetonitrile, tetrahydrofuran, dimethylformamide, 1,2-dichloroethane, dioxane, water, or the like.
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 0.5 to 24 hours.
• the compounds represented by the formula (15b) or (16b) can be prepared via the two steps shown in Preparation Scheme 4 mentioned above. Unless otherwise specifically indicated, R 1 to R 3 , R 13 , R 3" , R 4" , X and Ar mentioned in the Preparation Scheme mentioned above have the same meanings as those defined above. These preparation methods are divided into the first and second steps shown in Preparation Scheme 4, and the details of the methods will be explained for each step. The first step of preparing the compounds represented by the formula (15b) will be explained.
• a palladium catalyst that can be used for the usual Sohogasira reaction such as palladium(II) acetate, bis(benzonitrile)-dichloropalladium(II) and dichlorobis(triphenylphosphine)palladium(II) can be used.
• allylpalladium chloride dimer may be used in an amount of 0.05 to 0.6 equivalent.
• the base used may be diisopropylamine, triethylamine, dicyclohexylmethylamine, diisopropylmethylamine, piperidine, or the like.
• 1,4-diazabicyclo[2.2.2.]octane may be used in an amount of 1 to 5 equivalents.
• copper iodide(I) used for the usual Sonogashira reaction as an additive may be used in an amount of 0.1 to 1.2 equivalents.
• a phosphine ligand such as palladium(II) acetate and allylpalladium chloride dimmer is used, a phosphine ligand such as triphenylphosphine is preferably used, and tri-t-butylphosphine is preferably used in an amount of 0.1 to 1.5 equivalents.
• the halide used may preferably have a halogen atom on a suitable aromatic ring or heterocyclic ring, and preferably be used in an amount of 1 to 10 equivalents.
• the halogen atom may be chlorine atom or iodine atom. Bromine atom is preferred.
• the solvent may be 1,4-dioxane, dimethylformamide, tetrahydrofuran, benzene, or the like.
• acetonitrile may be used in an amount of 1 to 50 times (V/W) based on the amount of the compound represented by the formula (14b).
• the reaction progresses at a temperature in the range of 20 to 90°C, and the reaction time may be 1 hour to 10 days.
• the second step of preparing the compounds represented by the formula (16b) will be explained. These compounds are provided by subjecting a compound represented by the formula (15b) to catalytic hydrogen reduction.
• palladium/calcium carbonate deactivated with lead acetate is preferably used in an amount of 10 to 120% (W/W) based on the amount of the compound represented by the formula (15b).
• 1,4-dioxane may be used as a single solvent, or may be used as a mixed solvent with water. The reaction progresses at a temperature in the range of 20 to 50°C under a hydrogen atmosphere of 1 to 5 atm, and the reaction time may be 1 hour to 6 days.
• the compounds represented by the formula (15a), (16a), (15b) or (16b) prepared according to the methods of Preparation Schemes 3 and 4 can be converted into the compounds represented by the formulas (12a) and/or (13a), or by the formulas (12b) and/or (13b) by using the same method as the method of the seventh step of Preparation Scheme 1 or the fourth step of Preparation Scheme 2.
• the first step of preparing the compounds represented by the formula (11d) will be explained. These compounds are provided by removing 4-methoxybenzyl group at the 11-position in a compound represented by the formula (11c) prepared according to the first to sixth steps of Preparation Scheme 1 or the first to third steps of Preparation Scheme 2 by catalytic hydrogen reduction.
• the catalyst used for this reaction may be palladium black, palladium hydroxide, or the like.
• palladium/carbon may be used in an amount of 10 to 150% (W/W) based on the amount of the compound represented by the formula (11c).
• the solvent a single solvent of a lower alcohol such as methanol, ethanol and isopropanol, dioxane, water, acetonitrile, tetrahydrofuran, or the like may be used, or a mixed solvent consisting of a combination of these may be used. Ethyl acetate is preferably used.
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 5 hours to 3 days.
• the second step of preparing the compounds represented by the formula (11e) will be explained. These compounds are provided by subjecting a compound represented by the formula (11d) to a reductive alkylation reaction, which is performed by adding a suitable aldehyde in ethanol in the presence of acetic acid and using sodium cyanoborohydride as a reducing agent.
• the reducing agent used in this reaction may be sodium triacetoxyborohydride, sodium borohydride, or the like.
• sodium cyanoborohydride may be used in an amount of 1 to 10 equivalents.
• the aforementioned aldehyde is preferably used in an amount of 1 to 2 equivalents, and the acid added may be hydrochloric acid, or the like.
• acetic acid may be used in an amount of 1 to 10 equivalents.
• the solvent may be ethanol, as well as a lower alcohol such as methanol and isopropanol, acetonitrile, tetrahydrofuran, methylene chloride, 1,2-dichloroethane, or the like.
• the reaction progresses at a temperature in the range of 0 to 50°C, and the reaction time may be 0.5 to 48 hours.
• the compounds represented by the formula (11e) prepared according to the methods of Preparation Scheme 5 can be converted into the compounds represented by the formulas (12a) and/or (13a), or by the formulas (12b) and/or (13b) by using the same method as the seventh step of Preparation Scheme 1, or the fourth step of Preparation Scheme 2.
• the methods for preparing the compounds of the present invention are not limited to the methods explained above or the methods specifically described in the examples, and the compounds prepared by any methods also fall within the scope of the present invention.
• any compounds fall within the scope of the present invention which are obtainable by syntheses, preparations, extractions and purifications based on the aforementioned general explanations and specific explanations in the examples with modifications by known means.
• the compounds of the present invention form salts with various bases or acids, and this property is used for manufacture of pure substances and forms for supply as medicaments. More specifically, in the manufacture, they can be solubilized in a polar solvent such as water by acidification, for example, and isolated by extraction and purification as a form of a salt having favorable physicochemical properties.
• the compounds may be in a form of a pharmaceutically acceptable salt.
• a substance in any forms mentioned above may be used as an active ingredient of the medicament of the present invention.
• Forms of the salts formable by the compounds of the present invention are not particularly limited.
• a form of a pharmaceutically acceptable salt of the compound is preferred.
• examples of base addition salt include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, salts with ammonia or an appropriate non-toxic amine, C1-6 alkylamine (triethylamine and the like) salts, C1-6 alkanolamine (diethanolamine, triethanolamine and the like) salts, procaine salts, cyclohexylamine (dicyclohexylamine and the like) salts, benzylamine (N-methylbenzylamine, N-ethylbenzylamine, N-benzyl- ⁇ -phenethylamine, N,N-dibenzylethylenediamine, dibenzylamine and the like) salts, heterocyclic amine (morpholine, N-ethylpyridine, and the like) salts, and the like.
• acid addition salts include, for example, hydrogen halide acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like) salts, inorganic acid (sulfuric acid, nitric acid, phosphoric acid, perchloric acid, carbonic acid and the like) salts, carboxylic acid (acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, propionic acid, formic acid, malic acid and the like) salts, amino acid (alginic acid, aspartic acid, glutamic acid and the like) salts, organic acid (methanesulfonic acid, para-toluenesulfonic acid and the like) salts, and the like.
• hydrogen halide acid hydrofluoric acid, hydrochloric acid, hydrobro
• types of solvents are not particularly limited, and examples include, for example, water; alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran, and the like.
• the compounds of the present invention have two or more asymmetric carbons, and the configurations thereof are as shown in the aforementioned general formulas (the configurations in the formulas represent absolute configurations, and the indications of the configurations are according to those ordinarily used).
• the compounds of the present invention may sometimes have asymmetric carbon(s) in substituents.
• Arbitrary stereoisomers optical isomers, diastereoisomers
• arbitrary mixtures thereof racemates, mixtures of diastereomers
• a substance selected from the group consisting of the compounds of the present invention, pharmaceutically acceptable salts thereof, and solvates thereof can be administered to human or animals orally or parenterally (for example, intravenous injection, intramuscular injection, subcutaneous administration, intraperitoneal administration, rectal administration, transdermal administration).
• the medicament of the present invention which comprises the aforementioned substance as an active ingredient is prepared in a form of a suitable pharmaceutical composition depending on a route of administration.
• the medicament of the present invention can be prepared as a pharmaceutical composition, for example, as injections such as intravenous injection and intramuscular injection, oral agents such as capsules, tablets, granules, powders, pills, subtilized granules, and troches, agents for rectal administration, greasy suppository, aqueous suppository, and the like.
• compositions can be prepared in a conventional manner by using one or more kinds of pharmaceutical additives ordinarily used, for example, excipients, fillers, binders, wetting agents, disintegrating agents, surfactants, lubricants, dispersing agents, buffering agent, preservatives, dissolving aids, antiseptics, flavoring agents, soothing agents, stabilizers, and the like.
• pharmaceutical additives ordinarily used, for example, excipients, fillers, binders, wetting agents, disintegrating agents, surfactants, lubricants, dispersing agents, buffering agent, preservatives, dissolving aids, antiseptics, flavoring agents, soothing agents, stabilizers, and the like.
• excipients include, for example, lactose, fructose, glucose, cornstarch, sorbit, crystalline cellulose and the like
• disintegrating agents include, for example, starch, sodium arginate, gelatin, calcium carbonate, calcium citrate, dextrin, magnesium carbonate, synthetic magnesium silicate and the like
• examples of the binders include, for example, methylcellulose and salts thereof, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, polyvinylpyrrolidone and the like
• examples of the lubricants include, for example, talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil and the like
• examples of the other additives include, for example, syrup, vaseline, glycerol, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like
• a content of the active ingredient in the pharmaceutical composition may differ depending on a form of the composition.
• the content may generally be about 10 to 95% by weight, preferably 30 to 80 % by weight, of a total weight of the pharmaceutical composition.
• a dose is suitably determined considering a route of administration, age and sexuality of a patient, type of a disease, severity of symptoms and the like.
• the dose may generally be about 1 to 3000 mg, preferably 10 to 2000 mg, per day for an adult, and the aforementioned dose can be administered at one time or several times as divided portions in one day.
• N-(trans-4-tert-butyldimethylsilyloxy-2-pentenyl)-N-(4-phenylbutyl)amine was prepared by the method described below.
• this compound was dissolved in 23 ml of tetrahydrofuran under argon atmosphere, added with 4 ml of a 1.58 M solution of n-butyllithium in hexane at -78°C, stirred for 25 minutes, then added with 5.2 ml of a 1 M solution of zinc chloride in diethyl ether, then warmed to room temperature over 2 hours or more, added with 60 mg of tetrakis(triphenylphosphine)palladium dissolved in 7.5 ml of tetrahydrofuran and 0.68 ml of 1-bromo-3-iodobenzene, and further stirred for 92 hours.
• the reaction mixture was added with 20 ml of saturated aqueous ammonium chloride, warmed to room temperature, then diluted with 20 ml of ethyl acetate, and successively washed once with 20 ml of saturated aqueous ammonium chloride, and once with 20 ml of saturated brine.
• the organic layer was dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane) to obtain 79.2 mg of the title compound.
• R 1 is propionyl group
• R 2 is acetyl group
• R 3 is 4-phenylbutyl group
• R 5 , R 6 , R 7 and R 8 are hydrogen atoms
• R 4' is a group represented by the formula (a)
• R 3" is acetyl group
• R 4" is propionyl group
• X is -NR 4 - group
• R 4 is methyl group
• R 1 is propionyl group
• R 2 is acetyl group
• R 3 is methyl group
• R 5 , R 6 , R 7 and R 8 are hydrogen atoms
• R 4' is a group represented by the formula (a)
• R 3" is acetyl group
• R 4" is propionyl group
• X is -NR 4 - group
• R 4 is 4-phenylbutyl group
• R 2 are hydrogen atoms
• R 3 is methyl group
• R 5 and R 6 are hydrogen atoms
• E is a group represented by the formula (b)
• R 7 , R 8 , R 9 , R 10 and R 12 are hydrogen atoms
• R 11 is trans-3-(quinolin-3-yl)-2-propenyl group
• R 4' is a group represented by the formula (a)
• R 3" is propionyl group
• R 4" is n-butyryl group
• X is oxygen atom
• Example 63 (Stereoisomer of the compound of Example 57)
• Example 73 (Stereoisomer of the compound of Example 71)
• test substance prepared in methanol at a concentration of 6400 ⁇ g/l
• 2-fold serial dilutions were prepared by using methanol.
• Each of the prepared solutions of the test substances was put into a petri dish in a volume of 200 ⁇ l, added with 10 ml of agar medium for sensitivity measurement added with 5% horse sterile defibrinated blood, 15 ⁇ g/ml of ⁇ -nicotinamide-adenine dinucleotide, and 2.5 ⁇ g/ml of Hemin, and mixed for dilution to prepare an agar plate containing a test substance.
• antibacterial activities against gram positive bacteria 2 to 16 times of improvements of antibacterial activities against the test bacteria B and C were observed for the compounds of Examples 13, 28, 35, 43, 53 to 55, 64, 70, 84, 90, 94, 95, 108, 128, and 129 as compared with MDM.
• the antibacterial activities of the compounds of Examples 13, 28, 35, 43, 53, 54, 64, 70, 84, 90, 94, 95, 108, 128, and 129 against the test bacterium D were improved 8 to 1024 times or more as compared with MDM.
• the antibacterial activities against the test bacterium F of the compounds of Examples 13, 43, 53 to 55, 64, 70, 90, 94, 128, and 129 were improved 2 to 8 times as compared with MDM.
• the antibacterial activities against the test bacterium G of the compounds of Examples 13, 28, 43, and 64 were improved 2 to 4 times as compared with MDM.
• novel 14- to 16-membered ring azalide and 14- to 16-membered ring azalactam derivatives of the present invention have higher antibacterial activities against clinically important gram positive and gram negative bacteria than those of conventional antibacterial agents, and they are clinically highly useful as active ingredients of medicaments for prophylactic and/or therapeutic treatments of infectious diseases.

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